A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria

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2019-06-21

Tasmina Hydery University of Massachusetts Medical School

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Repository Citation Hydery T, Coppenrath VA. (2019). A Comprehensive Review of Pegvaliase, an Enzyme Substitution Therapy for the Treatment of Phenylketonuria. Open Access Articles. https://doi.org/10.1177/ 1177392819857089. Retrieved from https://escholarship.umassmed.edu/oapubs/3877

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Drug Target Insights A Comprehensive Review of Pegvaliase, an Enzyme Volume 13: 1–8 © The Author(s) 2019 Substitution Therapy for the Treatment of Article reuse guidelines: sagepub.com/journals-permissions Phenylketonuria DOI:https://doi.org/10.1177/1177392819857089 10.1177/1177392819857089 Tasmina Hydery1 and Valerie Azzopardi Coppenrath2 1Department of Family Medicine and Community Health, UMass Medical School—Clinical Pharmacy Services (CPS), Shrewsbury, MA, USA. 2School of Pharmacy—Worcester/Manchester, Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Worcester, MA, USA.

ABSTRACT

Objective: To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of a phenylalanine-metabolizing enzyme indicated to reduce blood phenylalanine concentrations, pegvaliase injection.

Data sources: Searches of MEDLINE (1946-September 1, 2018) were conducted using the terms pegvaliase and phenylalanine ammonia lyase (PAL). Additional data were obtained from the prescribing information, the product dossier obtained from the manufacturer, and Clinicaltrials.gov.

Study selection and data extraction: All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed.

Data synthesis: Pegvaliase is a pegylated PAL enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. Blood phenylalanine levels were reduced by approximately 50% to 70% in patients receiving therapeutic doses of pegvaliase. However, most patients experienced adverse events.

Conclusions and relevance: The mainstay of therapy in phenylketonuria (PKU) has historically consisted of dietary restriction of phenylalanine. Pegvaliase injection is the first Food and Drug Administration (FDA)–approved enzyme substitution therapy for patients with PKU. The therapy may be a viable option for patients with documented blood phenylalanine >600 µmol/L who have failed existing management strategies.

Keywords: Palynziq, pegvaliase, phenylalanine ammonia lyase, pegvaliase-pqpz, phenylketonuria, PKU

RECEIVED: May 22, 2019. ACCEPTED: May 23, 2019. Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this Type: Review article.

Funding: The author(s) received no financial support for the research, authorship, and/or CORRESPONDING AUTHOR: Tasmina Hydery, Department of Family Medicine and publication of this article. Community Health, UMass Medical School—Clinical Pharmacy Services (CPS), Shrewsbury, MA 01545, USA. Email: [email protected]

Introduction 360 µmol/L4,5 or 120 to 600 µmol/L, (van Wegberg, MacDonald Phenylketonuria (PKU) is a rare autosomal recessive condition and Ahring, 2017) therapy must be individualized to each patient. affecting about 1 in 13 500 to 19 000 people in the United Management of patients with HPA and PKU should be States.1 Phenylketonuria is diagnosed through detection of provided by an interdisciplinary team of nutritionists, elevated blood phenylalanine concentration.2 If untreated, psychologists, social workers, and metabolic specialists.2 PKU can cause chronic intellectual, neurodevelopmental, and Phenylketonuria is a relatively rare disease and patients may psychiatric disabilities. Excessive phenylalanine is thought to require lifelong treatment. The goal of therapy is to lower interfere with brain growth, myelination, and neurotransmitter blood phenylalanine concentrations to minimize the neuro- synthesis. Most cases of PKU are detected shortly after birth by cognitive and psychiatric effects of PKU.4–7 The mainstay of newborn screening. As a result, the severe signs and symptoms therapy is dietary restriction of phenylalanine and supplemen- of classic PKU are rarely seen.2 tation with phenylalanine-free medical foods to avoid nutri- Elevated phenylalanine levels are caused by a deficiency in the tional deficits.4–6 The medical foods are protein substitutes enzyme, phenylalanine hydroxylase (PAH).2 The spectrum of that are phenylalanine-free and fortified in tyrosine and may severity in untreated PKU ranges from complete enzyme defi- contain glycomacropeptides and other large neutral amino ciency or classic PKU (phenylalanine concentration > 1200 µmol/L), acids as the protein source.3 Adherence to the restrictive diet moderate PKU (phenylalanine concentration = 900-1200 µmol/L), requires planning and organization, and can be challenging for mild PKU (phenylalanine concentration = 600-900 µmol/L), and patients.4 mild hyperphenylalaninemia (HPA) (phenylalanine concentra- Sapropterin was Food and Drug Administration (FDA)– tion = 360-600 µmol/L).3 Although guidelines recommend life- approved on December 13, 2007, and was the first pharmaco- long treatment to a target blood phenylalanine level of 120 to logic therapy for treatment of PKU.8 It is an oral PAH cofactor

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Table 1. Summary of pharmacokinetic parameters studied.

Pharmacokinetic parameter Daily maintenance dosage

Pegvaliase 20 mg Pegvaliase 40 mg

Median Tmax 8 hours

Cmax at steady state (mean ± SD) 14.0 ± 16.3 mg/L 16.7 ± 19.5 mg/L

Apparent volume of distribution (mean ± SD) 26.4 ± 64.8 L 22.2 ± 19.7 L

Apparent clearance at steady state (mean ± SD) 0.39 ± 0.87 L/h 1.25 ± 2.46 L/h

Half-life (mean ± SD) 47 ± 42 hours 60 ± 45 hours

Steady state plasma concentrations during maintenance treatment (mean ± SD) 11.2 ± 9.0 mg/L 10.4 ± 12.7 mg/L

Metabolism Catabolic pathways, degraded into small peptides and amino acids

Abbreviations: Cmax, peak concentration; Tmax, time to peak concentration. indicated to reduce blood phenylalanine concentrations in Data Synthesis patients with HPA due to tetrahydrobiopterin (BH4)- Pharmacology responsive PKU. Sapropterin is used in conjunction with a phenylalanine-restricted diet.9 The efficacy of sapropterin is PAH catalyzes the irreversible conversion of phenylalanine based on the presence of residual PAH enzymatic activity. to tyrosine. In the absence of PAH in PKU, dietary phenyla- Approximately 25% to 50% of patients with PKU respond to lanine is unable to be converted to tyrosine and undergoes sapropterin.4 further processing to metabolites including L-dopa, thyrox- 13 Phase 3 trials for an enzyme substitution therapy for ine, dopamine, noradrenaline, adrenaline, and melanin. PKU began in 2013 and showed promise to be effective in There are 2 modes of enzyme therapy through replacement any patient with PKU regardless of residual enzymatic of the PAH enzyme or substitution with another enzyme to 12 activity.4 Pegvaliase, FDA-approved on May 24, 2018, acts degrade excess phenylalanine. Pegvaliase follows the latter as a substitute for the deficient PAH enzyme.10 Pegvaliase category and is a pegylated PAL enzyme that converts phe- 8 is indicated to reduce blood phenylalanine concentrations nylalanine to ammonia and trans-cinnamic acid. Ammonia in adult patients with PKU who have uncontrolled blood is metabolized by the liver. Trans-cinnamic acid and its final phenylalanine concentrations >600 µmol/L on existing product, benzoic acid, are conjugated with glycine and 13,14 management.11,12 excreted in the urine. Adult patients with PKU whose phenylalanine levels are not appropriately managed may experience adverse neurocog- Pharmacokinetics nitive and psychiatric outcomes.7 The objective of this article is Due to the heterogeneity of immune response in adults with to review the pharmacology, pharmacokinetics, efficacy, safety, PKU, the pharmacokinetics of pegvaliase exhibit high interpa- and place in therapy of pegvaliase injection. It will also provide tient and intrapatient variability. High antibody titers corre- an overview of the role of pegvaliase compared with current lated with higher apparent clearance. The pharmacokinetic standard of care. parameters are summarized in Table 1. Data Sources Clinical Trials A search of MEDLINE (1946-September 1, 2018) was conducted using the terms pegvaliase and phenylalanine ammonia Phase 1 lyase (PAL). The 2 terms were combined with the Boolean Clinical trial experience with pegvaliase is summarized in Table operator OR. The term pegvaliase was also searched on its 2. The first study of pegvaliase in humans was a phase 1, multi- own. All English language articles related to pharmacology, center, open-label study in patients over the age of 18 with a pharmacokinetics, efficacy, or safety of the therapy in human diagnosis of classic PKU (phenylalanine concentration subjects were included. The references of included articles >1200 µmol/L at diagnosis) and had a history of poor dietary were searched to identify additional sources. The product dos- compliance (PAL-001, NCT00634660). The average baseline sier was obtained from the manufacturer, and additional data phenylalanine concentration was 1310 µmol/L, and the average were obtained from the prescribing information and body mass index (BMI) was 26.4 kg/m2. Twenty-five patients Clinicaltrials.gov. were recruited from 7 centers in the United States. Patients were Hydery and Coppenrath 3

Table 2. Summary of trials of pegvaliase for the treatment of PKU in adults.

Phase Identifier Design Duration Dosing N Results

1 NCT00634660 OL, single dose 42 days 0.001, 0.003, 0.10, 0.03, 25 48.3% reduction in Phe from day 4 to 7 (PAL-001) and 0.100 mg/kg in the highest dosing group

2 NCT00925054 OL, multiple dose 16 weeks 0.001-0.1 mg/kg given 5 d/ 40 No significant changes in Phe (PAL-002) with induction and wk 5% (2 patients) discontinued due to titration phases AEs

2 NCT01212744 OL, multiple dose 13 weeks 0.06-0.8 mg/kg/d given 16 No significant changes in Phe (PAL-004) 5 d/wk 6.25% (1 patient) discontinued due to AEs

2 NCT01560286 OL, multiple dose 24 weeks 2.5 mg weekly × 24 46% reached maintenance dose (165-205) with induction, 4-8 weeks, then increased 56% reduction in Phe titration, and to a maximum of 75 mg 54% did not reach maintenance dose maintenance daily 8.33% (2 patients) discontinued due to phases AEs

2 NCT00924703 OL, multiple dose Extended Continued or increased 68a 58.9% reduction in Phe at 48 weeks (PAL-003) extension study follow-up of from parent studies, up to 72.3% reduction in Phe at 120 weeks phase 2 375 mg/wk given up to 7 d/ 5.9% (4 patients) discontinued due to studies to wk AEs 264 weeks

3 NCT01819727 OL, randomized 24 months 2.5 mg daily titrated to 261 51.1% reduction in Phe at 12 months (PRISM-1) multiple dose with either 20 or 40 mg daily 68.7% reduction in Phe at 24 months induction, titration, Improvement in mood and inattention and maintenance scores phases 11% (29 patients) discontinued due to AEs

3 NCT01889862 PRISM-1 extension (PRISM-2) studyb

Part 1 OL continuation of 20 or 40 mg daily Data not published PRISM-1

Part 2 R discontinuation 8 weeks 20 mg daily, 40 mg daily, 86 No change in Phe in the groups that study or placebo maintained doses 62.6% increase in Phe in placebo 20 mg group 56.4% increase in Phe in placebo 40 mg group No patients discontinued due to AEs

Part 3 OL, PD, PK 20 or 40 mg daily Data not published

Part 4 OL extension Ongoing 5-60 mg daily Ongoing

Abbreviations: AEs, adverse events; OL, open label; PD, pharmacodynamics; Phe, phenylalanine; PK, pharmacokinetic; PKU, phenylketonuria; R, randomized. aPatients from the other phase 2 studies. b12 patients from the phase 2 studies, but their data are not reported. excluded if they had renal or hepatic dysfunction, had pregnancy Phase 2 or potential pregnancy, or used nicotine, drugs of abuse, or any 15 The optimal dosing regimens were explored in 3 phase 2 stud- investigational products in the 30 days prior to screening. Twenty-five patients were assigned to 1 of 5 dosing groups ies of pegvaliase. PAL-002 (NCT00925054) was an open- in which they received a single subcutaneous injection of peg- label, multicenter study of 40 adults with PKU. Patients entered valiase on day 1: 0.001, 0.003, 0.10, 0.03, and 0.100 mg/kg. an 8-week induction phase of various fixed and weight-based Patients were followed up for 42 days. In the patients who doses of pegvaliase administered weekly, followed by an 8-week received the 0.1 mg/kg dose, pegvaliase significantly reduced titration phase during which increasing doses of pegvaliase phenylalanine concentrations (1113 to 575 mmol/L, mean were administered weekly with the goal of achieving reduced reduction of 48.3%) on day 6. Phenylalanine concentrations blood phenylalanine concentrations. The doses ranged from increased from day 7 to day 21 and remained relatively consist- 0.001 to 0.1 mg/kg throughout the study. These doses were not ent through the end of the study.15 sufficient to lower phenylalanine concentrations. 4 Drug Target Insights

PAL-004 (NCT01212744) was an open-label, multicenter mean blood phenylalanine concentration reached <600 µmol/L study of 16 adults with PKU. Patients were given doses of peg- by week 11 of the study. The mean reduction from baseline was valiase 5 d/wk which ranged from 0.06 to 0.8 mg/kg through- 627 ± 432 µmol/L (56% ± 36% reduction). Furthermore, all out the 13 weeks of the study. Similar to PAL-002, the doses patients in group A reached a blood phenylalanine concentra- studied resulted in inadequate control of blood phenylalanine tion target of <120 µmol/L during the 24-week study. Group levels. All patients in both studies experienced at least 1 adverse A had lower anti-drug antibody responses, which was likely event (AE). The regimens used in PAL-002 were generally associated with less immune-related clearance compared with well tolerated, but the higher doses in PAL-004 were associ- patients in group B with higher anti-drug antibody responses. ated with more frequent hypersensitivity reactions (which Ten of the 13 patients in group B continued on to the exten- included arthralgia, arthritis, eye inflammation, eye irritation, sion study, during which they achieved a blood phenylalanine eye pain, joint stiffness, joint swelling, pyrexia, vision blurred, concentration of ⩽600 µmol/L by week 48.17 and polyarthritis) and the need for dose reduction.16 Patients in the 3 phase 2 dosing finding studies (will be Based on observations made in PAL-002 and PAL-004, a referred to hereon in as “parent studies”) were invited to continue third phase 2 study, 165-205 (NCT01560286), was conducted. on in an extension study (PAL-003, NCT00924703) if they were This study was an open-label, multicenter study that was willing to continue stable protein intake. Patients taking any 24 weeks in duration. Patients were eligible if they had a blood other injectable drug containing polyethylene glycol (PEG) and phenylalanine concentration of ⩾600 µmol/L at screening and patients with a history of systemic hypersensitivity events to a an average concentration of ⩾600 µmol/L in the 6 months prior PEG-containing product were excluded. However, patients with to the screening, and no prior treatment with sapropterin in the a previous reaction to pegvaliase could be eligible for the study on 4 months prior to screening. Patients who were pregnant, plan- a case by case basis. Doses for individuals were either continued ning to become pregnant, or breastfeeding were excluded. from the parent study or increased and were adjusted throughout Patients entered a 4- to 8-week induction phase of 2.5 mg/wk. the study to attain or maintain phenylalanine concentrations Afterward, the dose and frequency could be increased over a between 60 and 600 µmol/L. In addition, doses could be adjusted minimum of 4 weeks to attain a blood phenylalanine concentra- to manage AEs. Initially, dosing ranged from 2.5 to 375 mg/wk tion of ⩽600 µmol/L. The authors defined the “maintenance or 0.001 to 5 mg/kg/wk, but a protocol changed limited weekly dose” as the regimen that resulted in target concentrations for dosing to 375 mg/wk. The authors used a modified intention-to- 4 weeks without the need for dose adjustments. Once the main- treat analysis for efficacy which included all patients who received tenance dose was determined, patients entered the next phase. 1 dose of pegvaliase and had at least 1 phenylalanine concentra- In the maintenance phase, the maintenance dose was continued tion measurement taken after treatment.17 but could still be adjusted for safety or to maintain concentra- Sixty-eight of the 80 participants in the parent studies enrolled tions below 600 µmol/L. The maximum dose in the mainte- in the extension study. The baseline phenylalanine concentration nance phase was 75 mg/d given 5 d/wk. However, the protocol was 1022.4 µmol/L. The mean daily dose of pegvaliase in the par- was updated to change the maximum frequency to 7 d/wk. ent studies was 5.3 mg/d (SD = 6.8 mg/d), and this increased to Patients experiencing severe hypersensitivity adverse events 26.2 mg/d (SD = 17.9 mg/d) in the extension study. Doses (HAEs) had their dosing interrupted or adjusted and restarted remained relatively stable from week 48 to week 120 of the study. at the same or a lower dose. Another protocol change allowed The average duration of treatment in all of the phase 2 studies patients with treatment-related acute systemic hypersensitivity was approximately 3.4 years. Mean phenylalanine concentrations events to permanently discontinue the study drug. The investi- decreased throughout the study by more than half (58.9%) at gators used a modified intention-to-treat analysis consisting of week 48 of treatment and by 72% at week 120 (1022.4 µmol/L at participants who received at least 1 dose of the study drug and baseline, 541.6 µmol/L at week 48, and 372 µmol/L at week had at least 1 post-treatment blood phenylalanine level.17 120).17 Twenty-four patients enrolled in the study, with 11 patients Approximately one-third of patients (36.8%) had their peg- achieving maintenance dose in the first 24 weeks (group A) and valiase dosing reduced or held during the study. A small number 13 patients not achieving maintenance dose within 24 weeks of patients (n = 4, 5.9%) discontinued the study due to AEs. All (group B). Patients had a mean age of approximately 29 years, 4 patients reported resolution of the AEs after discontinuing and baseline blood phenylalanine concentrations were similar treatment. Hypersensitivity adverse events were highest during in both groups (1134.8 µmol/L in group A vs 1197.5 µmol/L in early treatment in phase 2 studies and correlated with the tim- group B). However, group A was comprised mostly of women ing of highest IgM, PEG IgM, and PEG IgG antibodies.17 with a mean weight of 64.6 kg, whereas group B was mostly men with a mean weight of 86.4 kg. Baseline total protein Phase 3 intake and dietary phenylalanine intake were higher in group B. Mean doses of pegvaliase in the 24-week study were 64.7 mg Pegvaliase was evaluated in a phase 3 study, PRISM-1 in group A and 89.4 mg in group B. The group A patients’ (NCT01819727). In this multicenter, open-label study, patients Hydery and Coppenrath 5 naïve to pegvaliase were randomized to receive 1 of 2 regimens in to part 4 of PRISM-2, in which the open-label dosing of pegvaliase. Patients with a blood phenylalanine concentra- ranges from 5 to 60 mg daily.18 tion of 600 µmol/L or higher for at least 6 months prior to the Eighty-six patients who received pegvaliase in PRISM-2 study were eligible. It is unclear if allocation to treatment part 1 enrolled in the double-blinded PRISM-2 part 2 discon- groups was concealed. Both groups received 2.5 mg once per tinuation trial. An additional 9 patients were enrolled but were week of pegvaliase subcutaneously for 4 weeks during the not included in the efficacy analysis. Patients were randomized induction period. Dosing and frequency were increased gradu- via concealed allocation to receive either their current pegvali- ally to either 20 mg/d or to 40 mg/d. Titration was performed ase dose (either 20 or 40 mg/d) or matched placebo containing over a period of 5 to 30 weeks. The schedule was described for either 20 mg or 40 mg of Dextran 40 (22% Dextran 40). The the 20 mg/d group: 2.5 mg twice weekly, 10 mg weekly, 10 mg study drugs were self-administered daily for 8 weeks, rotating twice weekly, 10 mg 4 times weekly, 10 mg daily, and then subcutaneous injection sites.19 20 mg daily. Doses were continued in the maintenance phase, The pooled active pegvaliase group phenylalanine concen- which ranged from 24 to 36 weeks in duration. Phenylalanine trations remained stable from baseline to week 8 (503.9- levels, safety, immunogenicity, and neuropsychiatric symptoms 559 µmol/L), while levels in both placebo groups increased were assessed by trained study staff at each site using tools vali- (563.9-1509 µmol/L in the placebo 20 mg group and 508.2- dated for use in PKU.18 1164.4 µmol/L in the placebo 40 mg group). However, no sig- PRISM-1 included 261 patients: 131 in the 20 mg/d group nificant changes in mood or inattention were observed, perhaps and 130 in the 40 mg/d group. Patients had a mean age of due to the short duration of the trial or to the tools used to approximately 30 years at baseline and were mostly white, and measure these symptoms in the trial.19 Patients in PRISM-1 approximately half of them were women. Mean phenylalanine demonstrated improvements in attention deficit hyperactivity levels at baseline were 1232.7 µmol/L. The mean number of disorder (ADHD) scores at 3 months of treatment.16 weeks to reach maintenance doses was 11.5 and 14 in the Overall, clinical trial experience from phase 1 to phase 3 20 mg/d and 40 mg/d groups, respectively.18 suggests substantial reductions in blood phenylalanine concen- Mean phenylalanine concentrations decreased by 51.1% trations and improvement in inattention and mood symptoms from baseline to 564.5 µmol/L at 12 months of follow-up, and with the use of pegvaliase. However, these benefits must be by 68.7% from baseline to 311.4 µmol/L at 24 months of fol- weighed against the risk of common and sometimes serious low-up. Inattention and mood scores improved while on treat- AEs. ment with pegvaliase and correlated with a decrease in phenylalanine levels. Similar to previous studies, all patients Dosing and Administration experienced at least 1 AE. However, in this study, 99% of events The package insert for Palynziq recommends to obtain base- were mild to moderate in nature, and 96% resolved without line blood phenylalanine concentrations prior to treatment ini- dose reduction or interruption. This represents an improve- tiation.11 The induction dosage for pegvaliase is 2.5 mg ment in the safety profile compared with previous regimens subcutaneously once weekly for 4 weeks under the supervision studied. The most common AEs were arthralgia (70.5%), of a health care provider. The dosage should be titrated based injection site reactions (62.1%), injection site erythema (47.9%), on tolerability over at least 5 weeks to achieve a dosage of 20 mg and headache (47.1%). Of the AEs leading to discontinuation, subcutaneously once daily. Therapeutic response may not be 2.7% were anaphylaxis, 2.7% were arthralgia, 1.1% were injec- achieved until the patient is titrated to an effective mainte- tion site reactions, and 0.8% were generalized rash. Twelve nance dose. patients (4.6%) experienced 1 or more acute systemic HAEs During treatment, patient tolerability, blood phenylala- which were independently adjudicated by an allergist/immu- nine concentrations, dietary protein, and phenylalanine nologist. The median time after pegvaliase administration to intake should be monitored. Studies in adult PKU patients acute systemic HAE was 1.8 minutes, and all occurred within have shown a variation in phenylalanine levels can be the first 50 days of dosing and were resolved quickly.18 observed without any change in treatment.20 In clinical trials, Patients enrolled in PRISM-1 could continue to PRISM-2 the response to sapropterin treatment was defined as a 30% (NCT01889862), a study to evaluate the safety and efficacy of reduction in blood phenylalanine concentration from base- long-term treatment. Patients reaching maintenance dosing in line.21 In contrast, therapeutic response with pegvaliase was PRISM-1 entered part 1 of PRISM-2, and continued their based on a 20% reduction in blood phenylalanine concentra- assigned doses, either 20 mg or 40 mg daily. Part 2 was a rand- tion from baseline or a blood phenylalanine concentration omized, double-blinded, placebo-controlled discontinuation ⩽600 µmol/L after 24 weeks. If not achieved, increasing the study which will be described below. Part 3 was an open-label pegvaliase dose to a maximum dosage of 40 mg subcutane- pharmacodynamics and pharmacokinetic study, and part 4 is an ously once daily can be considered. If therapeutic response open-label extension study which is ongoing. Patients who did has not been achieved after 16 weeks on the maximum dos- not reach maintenance dosing in PRISM-1 could enter directly age, discontinuation of pegvaliase is recommended. If 6 Drug Target Insights patients experience blood phenylalanine concentrations treatment with sapropterin, a test should be conducted to <30 µmol/L during titration and maintenance, the dosage of determine if the patient is sapropterin-responsive, defined as a pegvaliase may be reduced or the dietary protein and pheny- rapid decline in phenylalanine or increase in phenylalanine tol- lalanine intake may be modified.11 erance. Sapropterin can provide better phenylalanine control For hypersensitivity reactions, premedication can be consid- and increase dietary phenylalanine tolerance.25 Clinical guide- ered with an H1-receptor antagonist, H2-receptor antagonist, lines have recently been updated on to address the role of peg- and/or antipyretic prior to administration based on tolerability. valiase in management of PKU. The goal of pegvaliase Patients should be observed during and for at least 60 minutes treatment is to provide maintenance of blood phenylalanine after receiving pegvaliase injection. Patients should also be concentrations while normalizing diet. Pegvaliase can be con- trained on recognition of signs and symptoms of anaphylaxis, sidered for all adult patients with PKU who can adhere to how to administer injectable epinephrine, and how to seek therapy, including requirement for monitoring of AEs.26 No emergency care, if needed. If the decision is made to readmin- head-to-head trials were conducted comparing the safety and ister pegvaliase after an episode of anaphylaxis, the subsequent efficacy of sapropterin with pegvaliase. Given patients in the dose should be administered under the supervision of a health clinical trials were unable to continue sapropterin in the peg- care provider after titrating based on patient tolerability and valiase trials, it is unclear whether the combination is statisti- therapeutic response.11 cally and clinically more beneficial than either treatment alone. Due to the risks of anaphylaxis, pegvaliase is only available Although the package insert for pegvaliase does not specify through a Risk Evaluation and Mitigation Strategies (REMS) use to be in conjunction with a phenylalanine-restricted diet, it is program which includes prescriber and pharmacy certification indicated in patients with uncontrolled blood phenylalanine requirements and patient educational enrollment. In clinical concentrations “on existing management”11 which can be trials, most patients developed anti-PEG IgM and IgG anti- inferred as guideline-recommended dietary therapy and/or sap- bodies after treatment. The clinical effects of concomitant ropterin pharmacotherapy. Furthermore, in pegvaliase clinical treatment with other pegylated products are unknown. trials, patients were stable in protein intake and in many instances Therefore, if patients are treated in combination with other received counseling from a dietician.15–19 However, while pegylated products, further monitoring for hypersensitivity Thomas et al observed stable total dietary protein intake, there reactions and anaphylaxis is recommended.11 was a decrease in medical food protein (from 26.3 to 18.4 g/d) and an increase in dietary phenylalanine intake (from 1700.2 to Relevance to Patient Care and Clinical Practice 2679.7 mg/d). This shift may indicate a decreased need for med- The risk of adverse outcomes in PKU is related to disease sever- ical food.18 Efficacy of pegvaliase without dietary therapy was ity, blood phenylalanine concentration, and adherence to treat- not assessed in clinical trials. Due to the potential shifts in dos- 4 ment. The assessment of blood phenylalanine concentrations ing from changing dietary protein and phenylalanine intake, 22 may also be indicative of patient adherence to therapy. Poor continuation of nutritional and blood phenylalanine monitoring adherence can manifest as failure to take medical foods or pre- is warranted in patients treated with pegvaliase.11,26 scribed medications, and missing regular clinic appointments or Given only 25% to 50% of patients with PKU respond to 23 blood phenylalanine testing. A presentation released by sapropterin,3 the availability of additional pharmacologic BioMarin Pharmaceuticals suggests there are 125 PKU clinics options is necessary to improve the quality of life in patients in the United States currently managing patients through die- with uncontrolled PKU. In 2015, the National PKU Alliance 24 tary counseling and/or sapropterin. A study of 45 PKU clinics conducted a survey of adults and children with PKU in the showed that non-adherence to clinic-recommended target phe- United States. The survey confirmed that dietary therapy is the nylalanine concentrations increased with age. Most adults had mainstay of clinical treatment. Approximately 6% of survey > blood phenylalanine concentrations 360 µmol/L with 15% of respondents stated they were not treating PKU with medical + patients aged 18 to 29 years and 20% of patients aged 30 years foods or pharmacotherapy. Most survey respondents (91%) > 23 reported to have concentrations 1200 µmol/L. Given that stated the importance of development of new products for PKU can cause neurocognitive and psychiatric symptoms, there PKU. Respondents generally preferred oral therapy over inject- may be an unmet need for additional therapeutic approaches in able therapy, and home injections over injections, at a medical adults with uncontrolled disease. facility.27 Pegvaliase is a novel enzyme substitution therapy Dietary treatment consists of dietary restriction of phenyla- which can be used in patients with more severe disease and in lanine, phenylalanine-free protein substitutes (l-amino acid part meets the needs of the PKU community. The subcutane- 4,6 mixtures), and modified low-protein foods. Patients with ous prefilled syringe can be self-administered if patients dem- residual enzymatic activity of PAH may respond to sapropterin onstrate adequate competency.11 Although an oral pegylated which increases metabolism of phenylalanine to tyrosine. PAL formulation has been investigated in animal studies,28 Safety and efficacy of sapropterin have been established in similar trials have not been conducted in humans. It is recom- 21 pediatric patients as young as 1 month of age. Prior to routine mended that multidisciplinary teams continue involvement in Hydery and Coppenrath 7 care of patients with PKU, including monitoring therapeutic Informed Consent response, adverse effects, and medication adherence. Given the writing of this review article was non-human subject research and based on the availability of published clinical trial Cost data, written/verbal consent from patients and/or caregivers was not necessary. As of June 2018, pegvaliase has been launched. For cost consid- erations, the average wholesale price (AWP) for pegvaliase- ORCID iD pqpz prefilled syringes are US$585.60 which includes 3 Tasmina Hydery https://orcid.org/0000-0002-7206-1668 strengths: 2.5 mg/0.5 mL, 10 mg/0.5 mL, and 20 mg/mL, whereas the AWP of sapropterin 100 and 500 mg tablets are US$44.28 and US$221.40 per tablet, respectively.29,30 Using References 1. National Institutes of Health Consensus Development Panel. National Insti- these AWP cost figures, the 30-day cost for a 70 kg patient at tutes of Health Consensus Development Conference Statement: phenylketon- the maximum recommended sapropterin dose (20 mg/kg once uria: screening and management, October 16–18, 2000. Pediatrics. 2001; daily) is US$5314 and at the maximum recommended pegvali- 108:972. 2. Bodamer OA, Hahn S, TePas E. Overview of phenylketonuria. In: Basow, DS, ase-pqpz dose (40 mg once daily) is US$35 136. BioMarin ed. UpToDate [database on the internet]. Waltham, MA: UpToDate; 2018. Pharmaceuticals predicts the average annual net cost of therapy http://www.utdol.com/utd/index.do. Accessed June 19, 2018. 3. Scriver CR, Kaufman S. The hyperphenylalaninemias. Phenylalanine hydroxy- for a typical patient to be approximately US$192 000 per year lase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic based on an average of 1.5 units per patient at maintenance and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill; 24 2001:1667. dosing. Dietary treatments used in conjunction with cur- 4. Vockley J, Andersson HC, Antshel KM, et al. Phenylalanine hydroxylase defi- rently available pharmacotherapy pose an additional cost bur- ciency: diagnosis and management guideline. Genet Med. 2014;16:188–200. doi:10.1038/gim.2013.157. den to patients and payers. 5. Abadie V, Berthelot J, Feillet F, et al. [Management of phenylketonuria and hyperphenylalaninemia: the French guidelines]. Arch Pediatr. 2005;12:594. Conclusions doi:10.1016/j.arcped.2005.02.004. 6. van Wegberg AMJ, MacDonald A, Ahring K, et al. The complete European Patient characteristics and preferences should be considered to guidelines on phenylketonuria: diagnosis and treatment. Orphanet J Rare Dis. help guide treatment of PKU. Pegvaliase reduces blood pheny- 2017;12:162. doi:10.1186/s13023-017-0685-2. 7. van Spronsen FJ, Burgard P. The truth of treating patients with phenylketonuria lalanine concentrations independent of PAH activity compared after childhood: the need for a new guideline. J Inherit Metab Dis. 2008;31:673- 4 with previously available therapeutic alternatives. In pivotal 679. doi:10.1007/s10545-008-0918-6. phase 3 clinical studies, treatment with pegvaliase was associ- 8. BioMarin Announces FDA Approval for Kuvan. BioMarin. https://investors. biomarin.com/2007-12-13-BioMarin-Announces-FDA-Approval-for-Kuvan. ated with overall safety and statistically significant improve- Accessed September 26, 2018. ments in blood phenylalanine concentrations.18,19 Patients also 9. Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2015;3:CD008005. doi:10.1002/14651858. had sustained reductions in blood phenylalanine concentra- CD008005.pub4. tions that reached guideline-recommended levels. However, 10. FDA approves a new treatment for PKU, a rare and serious genetic disease. Food and Drug Administration. https://www.fda.gov/newsevents/newsroom/pres- due to risks of anaphylaxis, pegvaliase is only available through sannouncements/ucm608835.htm. Accessed September 26, 2018. a restricted program under REMS.11 The injectable route of 11. Palynziq® [package insert]. Novato, CA: BioMarin Pharmaceutical Inc; May 2018. administration, potential risks, and factors related to insurance 12. Palynziq® (pegvaliase-pqpz) formulary dossier. BioMarin, Data on file. coverage may limit the use of pegvaliase. At the present time, 13. Bell SM, Wendt DJ, Zhang Y, et al. Formulation and PEGylation optimization pegvaliase is only FDA-approved for use in adults who have of the therapeutic PEGylated phenylalanine ammonia lyase for the treatment of phenylketonuria. PLoS ONE. 2017;12:e0173269. doi:10.1371/journal. uncontrolled blood phenylalanine concentrations pone.0173269. >600 µmol/L.11 Clinical guidelines have been updated to 14. Sarkissian CN, Shao Z, Blain F, et al. A different approach to treatment of phe- 26 nylketonuria: phenylalanine degradation with recombinant phenylalanine address the role of pegvaliase in management of PKU. Given ammonia lyase. Proc Natl Acad Sci U S A. 1999;96:2339–2344. doi:10.1073/ the high cost, therapy may be a viable option for patients who pnas.96.5.2339. 15. Longo N, Harding CO, Burton BK, Grange DK, et al. Single-dose, subcutane- have failed existing management strategies due to inadequate ous recombinant phenylalanine ammonia lyase conjugated with polyethylene response or desire for dietary relaxation. Further research glycol in adult patients with phenylketonuria: an open-label, multicenter, phase 1 dose-escalation trial. Lancet. 2014;384:37–44. doi:10.1016/S0140 should be conducted to evaluate the safety and efficacy in -6736(13)61841. younger patients, those with milder forms of PKU, in combina- 16. Thomas JA, Longo N, Zori R, Burton BK, et al. Evaluation of multiple dosing tion with sapropterin, and with limited dietary therapy. regimens in phase 2 studies of “rAvPAL-PEG” for control of blood phenylalanine levels in adults with phenylketonuria. 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Pegvaliase for the treatment of phe- permission was applied for. nylketonuria: a pivotal, double-blind randomized discontinuation phase 3 8 Drug Target Insights

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